Elevation of endogenous GABA by the racemic mixture of gamma vinyl- GABA (GVG, Vigabatrin®) decreases extracellular nucleus accumbens (NAc) dopamine (DA) levels and diminishes the response to many drugs of abuse known to elevate DA in the mesocorticolimbic system. We investigated the effects of the individual enantiomers (S(+)GVG, R(-)-GVG) on cocaine- induced NAc DA in rodents as well as the effects of nicotine-induced increases in primates. In a series of microdialysis experiments in freely moving animals, S(+)-GVG (150 mg/kg), R(-)-GVG (150 mg/kg) or racemic (R, S) GVG (300 mg/kg) was administered 2.5 hours prior to cocaine (20 mg/kg) administration. When compared with cocaine alone, the R(-) enantiomer did not significantly inhibit cocaine induced NAc DA release. S(+)-GVG, at half the dose of the racemic mixture (150 mg/kg), inhibited cocaine-induced DA elevation by 40%, while the racemic mixture (300 mg/kg) inhibited cocaine- induced DA release by 31%. In addition, our PET studies in primates demonstrated that S(+)GVG completely inhibits nicotine-induced increases in the corpus striatum, again at half the dose of the racemic mixture. The R(- ) enantiomer was ineffective. Although the S(+) enantiomer has been well established as the active compound in the treatment of epilepsy, the efficacy of this enantiomer with regard to mesolimbic DA inhibition generates a complex series of clinical and neurochemical issues. Further investigations will determine the locus of action and physiologic properties of each enantiomer. (C) 2000 Elasevier Science Inc.
Bibliographical noteFunding Information:
The authors gratefully acknowledgeC .R. Ashby, Jr, J. Fowler, N. Volkow, P. King, N. Pappas,C . Shea, R. MacGregor, R. Ferrieri and R. Carciello. The authors acknowledgeH oescht Marion Roussel for the supply of GVG and ChiroTech for the supply of each enantiomer. This research was carried out at Brookhaven National Laboratory under contract with the U.S. Departmento f Energy Office of Biological and Environmental Research (USDOE/OBER (DE-AC02-98CH10886) and by the National Institutes of Mental Health (NIMH MH49165 and NIMH R2955155).
- Gamma vinyl-GABA
- Positron emission tomography